Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society. This is an open access article under the terms
of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided
the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
LAY SUMMARY:
• Some tumors produce a protein called programmed death ligand 1 (PD-L1), which interacts with the body’s immune system and pre-
vents an immune response against cancer.
• Antibody therapies such as pembrolizumab block interactions between tumor PD-L1 and the immune system and enable an immune
response. Used alone, pembrolizumab provides benefit for patients with non–small cell lung cancer (NSCLC) tumors that produce PD-L1.
However, when it is combined with chemotherapy, which can stimulate anticancer immune responses, pembrolizumab provides a benefit,
regardless of tumor PD-L1 production.
• This article shows that among patients with NSCLC whose tumors produce no PD-L1, outcomes are better with pembrolizumab plus
chemotherapy in comparison with chemotherapy alone.
KEYWORDS: antineoplastic agents, combined drug therapy, non–small cell lung cancer, pembrolizumab, programmed cell death ligand
1 protein (human CD274 protein).
Corresponding Author: Hossein Borghaei, DO, Hematology and Oncology, Fox Chase Cancer Center, 333 Cottman Ave, Philadelphia, PA 19111 ([email protected]).
1 Hematology and Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania; 2 Department of Medicine, Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania; 3 Department of Medical Oncology, Hospital Universitario 12 de Octubre, Universidad Complutense and CIBERONC, Madrid, Spain; 4 Complejo Hospitalario Universitario Insular Materno-Infantil de Gran Canaria, Universidad de Las Palmas de Gran Canaria, Las Palmas de Gran Canaria, Spain; 5 Montefiore Einstein Center for Cancer Care, New York, New York; 6 Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; 7 Mid North Coast Cancer Institute, Port Macquarie Base Hospital, Port Macquarie, New South Wales, Australia; 8 Department of Thoracic Oncology, Kansai Medical University Hospital, Osaka, Japan; 9 Jilin Cancer Hospital, Changchun, China; 10 Merck & Co., Inc., Kenilworth, New Jersey; 11 Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan
We thank the patients and their families and caregivers for participating in the studies included in this pooled analysis along with all investigators and site personnel. Medical writing assistance was provided by Sheri Arndt, PharmD, and Mariana Ovnic, PhD, of ICON plc (North Wales, Pennsylvania). This assistance was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. (Kenilworth, New Jersey).
Additional supporting information may be found in the online version of this article.
DOI: 10.1002/cncr.33142, Received: June 9, 2020; Revised: July 9, 2020; Accepted: July 10, 2020, Published online Month 00, 2020 in Wiley Online Library
INTRODUCTIONThe anti–programmed death 1 (PD-1) monoclonal antibody pembrolizumab first showed increasing clinical efficacy with higher levels of programmed death ligand 1 (PD-L1) expression in patients with advanced non–small cell lung cancer (NSCLC) in the phase 1b KEYNOTE-001 study.1 Results from the phase 3 studies KEYNOTE-024 and KEYNOTE-042 for patients with PD-L1 expression on ≥50% of tumor cells (tumor proportion score [TPS] ≥ 50%)2 and for patients with a PD-L1 TPS ≥ 1%,3 respectively, subsequently established pembrolizumab monotherapy as a first-line standard of care for patients with PD-L1‒positive advanced NSCLC and no EGFR or ALK genomic tumor aberrations. On the basis of results from KEYNOTE-001, patients with PD-L1‒negative tu-mors (PD-L1 TPS < 1%) were not included in these studies, and they are not eligible for pembrolizumab monotherapy.
Chemotherapy agents have shown immunomod-ulatory properties, including directly and indirectly stimulating immune responses and increasing tumor im-munogenicity.4,5 Chemotherapy may also enhance the antitumor activity of immunotherapy4 and thus increase the likelihood of a clinical benefit with pembrolizumab, regardless of tumor PD-L1 expression. In cohort G of the multicohort, phase 1/2 KEYNOTE-021 study, a significantly higher objective response rate (ORR) was observed with pembrolizumab plus pemetrexed and carboplatin versus chemotherapy alone in patients with previously untreated advanced nonsquamous NSCLC and no sensitizing EGFR or ALK alterations.6 The ran-domized, placebo-controlled, phase 3 KEYNOTE-189 study, a larger confirmatory clinical trial, demonstrated significantly improved overall survival (OS) and progres-sion-free survival (PFS) with pembrolizumab plus peme-trexed and carboplatin or cisplatin versus placebo plus chemotherapy in patients with metastatic nonsquamous NSCLC without sensitizing EGFR or ALK alterations.7 In addition, the randomized, placebo-controlled, phase 3 KEYNOTE-407 study showed significantly improved OS and PFS with pembrolizumab plus carboplatin and pacl-itaxel or nab-paclitaxel versus placebo plus chemotherapy in patients with stage IV squamous NSCLC.8 Each of these studies demonstrated that the combination of pem-brolizumab and platinum-based chemotherapy improved clinical outcomes both for patients with PD-L1‒positive tumors (PD-L1 TPS ≥ 1%) and for patients with PD-L1‒negative tumors and had a manageable safety profile.6-8
As a result of these findings, pembrolizumab plus platinum-based chemotherapy is now a standard of care for the first-line treatment of patients with metastatic
NSCLC with no sensitizing EGFR or ALK alterations, re-gardless of histology or tumor PD-L1 expression.9 To fur-ther characterize the efficacy and safety of pembrolizumab plus chemotherapy versus chemotherapy alone in PD-L1‒negative advanced NSCLC, we performed a pooled analy-sis among patients with PD-L1‒negative tumors by using individual patient data from KEYNOTE-021 cohort G, KEYNOTE-189, and KEYNOTE-407.
MATERIALS AND METHODS
PatientsIndividual patient data were pooled from 3 interna-tional, multicenter, clinical randomized controlled tri-als in NSCLC: cohort G of the phase 1/2, open-label KEYNOTE-021 study (stage IIIB/IV, nonsquamous; NCT02039674) and the phase 3, double-blind, placebo-controlled metastatic NSCLC studies KEYNOTE-189 (nonsquamous; NCT02578680 and NCT03950674) and KEYNOTE-407 (squamous; NCT02775435).6-8
Eligibility criteria common to all 3 studies included age ≥ 18 years, histologically or cytologically confirmed advanced NSCLC, 1 or more measurable lesions accord-ing to Response Evaluation Criteria in Solid Tumors ver-sion 1.1,10 and an Eastern Cooperative Oncology Group performance status of 0 or 1. Exclusions included prior systemic treatment for advanced disease, symptomatic central nervous system metastases, active autoimmune disease requiring systemic immunosuppressive therapy ≤2 years before study treatment, and active interstitial lung disease or a history of pneumonitis that required gluco-corticoid treatment. Enrollment in KEYNOTE-021 co-hort G and KEYNOTE-189 also excluded patients with sensitizing EGFR or ALK genomic tumor aberrations. In all 3 studies, a tumor biopsy sample was required for the evaluation of PD-L1 status. Further details of the eligibil-ity criteria for each of these studies have been published previously.6-8 For each study, procedures were approved by an appropriate institutional review committee.
TreatmentPatients in cohort G of KEYNOTE-021 were randomized 1:1 either to pembrolizumab 200 mg every 3 weeks for 35 cycles (ie, 2 years) plus pemetrexed 500 mg/m2 and carbopl-atin area under the curve (AUC) 5 mg/mL/min every 3 weeks for 4 cycles followed by pemetrexed maintenance therapy or to pemetrexed and carboplatin alone.6 Randomization was stratified by PD-L1 TPS (<1% vs ≥1%).6
Patients in KEYNOTE-189 were randomized 2:1 to receive pembrolizumab 200 mg or placebo every 3 weeks for 35 cycles. Both treatment groups also received
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4 cycles of pemetrexed 500 mg/m2 and the investigator’s choice of carboplatin AUC 5 mg/mL/min or cisplatin 75 mg/m2 followed by pemetrexed maintenance ther-apy. Randomization was stratified by PD-L1 status (TPS < 1% vs TPS ≥ 1%), choice of platinum drug (carbopla-tin vs cisplatin), and smoking history (current/former vs never).7
Patients in KEYNOTE-407 were randomized 1:1 to receive pembrolizumab 200 mg or placebo every 3 weeks for 35 cycles. Both treatment groups also received 4 cy-cles of carboplatin AUC 6 mg/mL/min on day 1 and the investigator’s choice of either paclitaxel 200 mg/m2 on day 1 or nab-paclitaxel 100 mg/m2 on days 1, 8, and 15. Randomization was stratified by PD-L1 TPS (<1% vs ≥1%), choice of taxane (paclitaxel vs nab-paclitaxel), and geographic region (East Asia vs the rest of the world).8
In each of the 3 studies, pembrolizumab treatment was continued for up to 35 cycles or until disease pro-gression, unacceptable toxicity, a physician’s decision to discontinue treatment, or withdrawal of patient con-sent. Patients in the chemotherapy alone groups with radiological disease progression confirmed by blinded, independent, central review in KEYNOTE-189 and KEYNOTE-407 were eligible to cross over to open-label pembrolizumab monotherapy if protocol-specified safety criteria were met.6-8
AssessmentsAcross the 3 studies, PD-L1 expression was evaluated centrally in formalin-fixed tumor samples from newly bi-opsied tissue or archival specimens via the PD-L1 IHC 22C3 pharmDx assay (Agilent Technologies, Carpinteria, California).6-8 In KEYNOTE-189 and KEYNOTE-407, specimens provided after the diagnosis of metastatic dis-ease were preferred. Investigators were blinded to PD-L1 assessments.
Tumor imaging was performed at weeks 6 and 12 (and additionally at week 18 in KEYNOTE-021 cohort G and KEYNOTE-407); then every 9 weeks through the remain-der of the first year for KEYNOTE-021 cohort G, through week 48 for KEYNOTE-189, and through week 45 for KEYNOTE-407; and at 12-week intervals thereafter.6-8 In all 3 studies, response was assessed by blinded, indepen-dent, central radiological review.6-8,10 During follow-up, survival was assessed every 8 weeks in KEYNOTE-021 cohort G and every 12 weeks in KEYNOTE-189 and KEYNOTE-407. Adverse events (AEs) and laboratory findings were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0 (version 4.03 for KEYNOTE-407).6-8
EndpointsIn KEYNOTE-021 cohort G, the primary efficacy end-point was ORR, and the key secondary endpoint was PFS. In KEYNOTE-189 and KEYNOTE-407, PFS and OS were dual primary endpoints, and ORR and dura-tion of response (DOR) were key secondary endpoints. In all 3 studies, progression-free survival 2 (PFS-2), defined as the time from randomization to second/subsequent disease progression after the initiation of new anticancer therapy (including crossover to pembrolizumab) or death from any cause (whichever occurred first), was an explora-tory endpoint. PFS-2 events were characterized as follows: time of death for patients who did not receive or stopped second-line therapy without progressive disease and did not start third-line therapy, time of investigator-assessed disease progression that led to discontinuation of second-line therapy, and time of third-line therapy initiation in patients who stopped second-line therapy without disease progression. Patients without a PFS-2 event at the time of the data cutoff were censored at the time they were last known to be alive and without disease progression after the initiation of new anticancer therapy.
Statistical AnalysisThis analysis included patients from KEYNOTE-021 co-hort G, KEYNOTE-189, and KEYNOTE-407 who were determined to have PD-L1–negative tumors; patients with nonevaluable PD-L1 results were not included. Efficacy was analyzed in the pooled intention-to-treat population, and safety was analyzed in the pooled popu-lation of patients who received 1 or more doses of the study treatment. All analyses were descriptive. No α was assigned to this exploratory analysis.
The Kaplan-Meier method was used to estimate OS, PFS, DOR, and PFS-2. Hazard ratios (HRs) and 95% CIs for OS, PFS, and PFS-2 were provided on the basis of an unstratified Cox regression model with treatment as a covariate. Subgroup analyses of OS and PFS were based on an unstratified Cox regression model with treatment as a covariate. Analyses were performed with SAS (version 9.4; SAS Institute, Inc., Cary, North Carolina). The data cutoff dates were August 19, 2019, for KEYNOTE-021 cohort G; May 20, 2019, for KEYNOTE-189; and May 9, 2019, for KEYNOTE-407.
RESULTSOf the 1328 total patients enrolled in the KEYNOTE-021 cohort G, KEYNOTE-189, and KEYNOTE-407 stud-ies, 444 (33.4%) had PD-L1‒negative NSCLC and were included in this analysis (256 on pembrolizumab
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plus chemotherapy [nonsquamous, n = 155; squamous, n = 94; other, n = 7] and 188 on chemotherapy alone [nonsquamous, n = 83; squamous, n = 99; other, n = 6]; Fig. 1). Overall, 68.0% of the patients in the pooled analysis population were men, and 61.9% had a base-line Eastern Cooperative Oncology Group performance status of 1 (Table 1). Baseline brain metastases and liver metastases were present in 15.5% and 18.5%, respec-tively. The percentage of patients with nonsquamous histology was higher in the pembrolizumab plus chemo-therapy group than the chemotherapy alone group be-cause of the 2:1 randomization ratio in KEYNOTE-189; otherwise, baseline characteristics were generally similar between treatment groups (Table 1).
Among all 444 patients, 255 in the pembrolizumab plus chemotherapy group and 186 in the chemotherapy alone group received 1 or more doses of treatment (Fig. 1). Nine patients in the pembrolizumab plus chemotherapy group and 2 patients in the chemotherapy alone group com-pleted treatment; 16 and 3 patients, respectively, remained on treatment at the data cutoff date. The most common reasons for discontinuation were disease progression (pem-brolizumab plus chemotherapy, n = 144 [56.5%]; chemo-therapy alone, n = 139 [74.7%]) and AEs (n = 72 [28.2%]
and n = 22 [11.8%], respectively). When we excluded patients who remained on treatment, 105 of the 183 patients (57.4%) who initially received chemotherapy alone crossed over to pembrolizumab monotherapy on study and/or received anti‒PD-(L)1 therapy outside of crossover (3 patients received both pembrolizumab on study and subsequent anti‒PD-[L]1 therapy outside of crossover); 118 patients (64.5%) received any subsequent therapy. When we excluded patients who remained on treatment, 129 of 239 patients (54.0%) who initially received pem-brolizumab plus chemotherapy received subsequent ther-apy. The median time from randomization to the data cutoff was 28.0 months (range, 14.7-55.4 months).
EfficacyAt the time of the individual study data cutoffs, a total of 311 deaths had occurred among all 444 patients (70%) in the pooled PD-L1‒negative population. Pembrolizumab plus chemotherapy improved OS over chemotherapy alone (HR, 0.63; 95% CI, 0.50-0.79) with a median OS of 19.0 months (95% CI, 15.5-22.8 months) in the pembrolizumab plus chemotherapy group and a median OS of 11.4 months (95% CI, 9.4-13.5 months) in the chemotherapy alone group (Fig. 2A). The estimated
FIGURE 1. Summary of enrollment and patient disposition in the pooled analysis population of patients with advanced NSCLC and no PD-L1 expression (TPS < 1%). Patients were enrolled into KEYNOTE-021 cohort G (stage IIIB/IV nonsquamous NSCLC) between November 25, 2014, and January 25, 2016; into KEYNOTE-189 (stage IV nonsquamous NSCLC) between February 26, 2016, and March 6, 2017 (global study), and between August 7, 2017, and May 11, 2018 (Japanese extension study); or into KEYNOTE-407 (stage IV squamous NSCLC) between August 19, 2016, and December 28, 2017. *Patients with tumor samples that were nonevaluable for PD-L1 expression were excluded from this analysis. NSCLC indicates non–small cell lung cancer; PD-L1, programmed death ligand 1; TPS, tumor proportion score.
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12-month OS rates were 67.4% (95% CI, 61.3%-72.8%) and 47.9% (95% CI, 40.6%-54.9%), respec-tively, and the 24-month rates were 41.0% (95% CI, 34.6%-47.2%) and 25.4% (95% CI, 19.0%-32.3%), respectively. HR point estimates for OS favored pem-brolizumab plus chemotherapy versus chemotherapy alone across all subgroups analyzed (Fig. 2B).
At the time of the data cutoff, events of disease pro-gression or death had occurred in 386 of the 444 patients. Pembrolizumab plus chemotherapy improved PFS over chemotherapy alone (HR, 0.68; 95% CI, 0.56-0.83). The median PFS was 6.9 months (95% CI, 6.2-8.8 months) in the pembrolizumab plus chemotherapy group and 5.8 months (95% CI, 4.8-6.2 months) in the chemotherapy alone group (Fig. 3A). The estimated 12-month PFS rates were 32.8% (95% CI, 27.0%-38.7%) and 19.3% (95% CI, 13.9%-25.3%), respectively, and the 24-month rates were 17.1% (95% CI, 12.5%-22.4%) and 8.5% (95% CI, 4.8%-13.5%), respectively.
Pembrolizumab plus chemotherapy improved PFS-2 over chemotherapy alone (HR, 0.57; 95% CI, 0.46-0.70). The median PFS-2 was 14.5 months (95% CI, 12.6-15.9
months) in the pembrolizumab plus chemotherapy group and 9.1 months (95% CI, 7.6-10.2 months) in the che-motherapy alone group (Fig. 3B).
Among patients with PD-L1‒negative tumors, the ORR was higher with pembrolizumab plus chemother-apy (50.0%; 95% CI, 43.7%-56.3%) than chemother-apy alone (29.8%; 95% CI, 23.4%-36.9%). The median DORs were 8.5 months (range, 1.1+ to 46.0 months) and 6.9 months (range, 1.4+ to 30.1+ months), respec-tively (Table 2).
Among the 73 patients who crossed over to pem-brolizumab on study, the median OS from the time of the initiation of crossover pembrolizumab was 6.3 months (95% CI, 4.8-7.7 months), and the median PFS was 2.6 months (95% CI, 2.0-2.8 months).
Sixteen patients (6.3%) in the pembrolizumab plus chemotherapy group completed 2 years of treatment. The ORR among these patients was 87.5% (95% CI, 61.7%-98.4%); 2 patients had a complete response, 12 had a par-tial response, and 2 had stable disease. The median DOR was 46.0 months (range, 7.6-46.0 months), and the me-dian PFS was 47.4 months (95% CI, 15.9-47.4 months). The 3-year OS rate was 100%; all patients remained alive at the data cutoff.
SafetyAEs of any grade, regardless of attribution to study treat-ment by the investigator, occurred in 253 of 255 patients (99.2%) in the pembrolizumab plus chemotherapy group and in 184 of 186 patients (98.9%) in the chemotherapy alone group (Table 3). The most common AEs in both the pembrolizumab plus chemotherapy group and the chemotherapy alone group were anemia and nausea. AEs of grade 3 or higher occurred in 182 patients (71.4%) in the pembrolizumab plus chemotherapy group and in 134 patients (72.0%) in the chemotherapy alone group; 27 (10.6%) and 12 (6.5%), respectively, had AEs that led to death (Table 3 and Supporting Table 1). Thirteen patients (5.1%) in the pembrolizumab plus chemother-apy group and 3 patients (1.6%) in the chemotherapy alone group experienced treatment-related AEs leading to death (Table 3 and Supporting Table 1).
Immune-mediated AEs and infusion reactions of any grade occurred in 74 of 255 patients (29.0%) in the pembrolizumab plus chemotherapy group and in 23 of 186 patients (12.4%) in the chemotherapy alone group (Table 4). The most common immune-mediated AEs in the pembrolizumab plus chemotherapy group were hypo-thyroidism, pneumonitis, and hyperthyroidism. Two pa-tients (0.8%) in the pembrolizumab plus chemotherapy
TABLE 1. Demographics and Baseline Disease Characteristics in a Pooled Analysis of Patients With a PD-L1 TPS < 1%
Characteristic
Pembrolizumab + Chemotherapy
(n = 256)
Chemotherapy Alone
(n = 188)
AgeMedian (range), y 64.0 (34-87) 64.0 (37-82)<65 y, No. (%) 131 (51.2) 96 (51.1)
Male sex, No. (%) 169 (66.0) 133 (70.7)Region of enrollment, No. (%)
Europe 142 (55.5) 89 (47.3)North America 60 (23.4) 45 (23.9)East Asia 36 (14.1) 29 (15.4)Other 18 (7.0) 25 (13.3)
FIGURE 2. Kaplan-Meier estimates of OS among patients with no PD-L1 expression (TPS < 1%): (A) OS for patients who received pembrolizumab plus chemotherapy versus chemotherapy alone and (B) subgroup analysis of OS. ECOG indicates Eastern Cooperative Oncology Group; OS, overall survival; PD-L1, programmed death ligand 1; TPS, tumor proportion score.
A
B
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group had grade 5 events of pneumonitis; no patients in the chemotherapy group had grade 5 immune-mediated AEs or infusion reactions.
DISCUSSIONThis pooled analysis of 3 randomized controlled tri-als demonstrated a substantial clinical benefit and manageable safety profile with first-line pembroli-zumab plus platinum-doublet chemotherapy versus chemotherapy alone in patients with PD-L1‒negative NSCLC. Pembrolizumab plus chemotherapy substan-tially reduced the risk of death (HR for OS, 0.63) and improved the median OS by ~8 months (19.0 vs 11.4 months); it also improved PFS (HR, 0.68), PFS-2 (HR, 0.57), and ORR (50.0% vs 29.8%). Patients who
completed 2 years of treatment were among those who derived a long-term benefit from pembrolizumab plus chemotherapy; in this group, ORR was high, and all patients remained alive at the data cutoff. Together, these results support pembrolizumab plus chemo-therapy as a standard-of-care first-line treatment for patients with PD-L1‒negative advanced NSCLC with-out EGFR/ALK alterations.
Pembrolizumab plus platinum-based chemother-apy arguably constitutes the standard of care for patients with PD-L1‒negative advanced/metastatic NSCLC who are eligible for checkpoint inhibitors. In both the first-line setting2,3 and the second-line setting,11 pem-brolizumab monotherapy has demonstrated improved OS only among patients with a PD-L1 TPS ≥ 1%, with
FIGURE 3. Kaplan-Meier estimates of PFS among patients with no PD-L1 expression (TPS < 1%): (A) PFS for patients who received pembrolizumab plus chemotherapy versus chemotherapy alone and (B) PFS-2 for patients who received pembrolizumab plus chemotherapy versus chemotherapy alone. PD-L1, programmed death ligand 1; PFS, progression-free survival; PFS-2, progression-free survival 2; TPS, tumor proportion score.
A
B
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further benefits observed among those with PD-L1 TPS ≥ 50%.3,11 Previously, bevacizumab and necitumumab were the only biologics/targeted agents to have demonstrated an improvement in OS (by ~2 months) when combined with platinum chemotherapy in patients with advanced nonsquamous NSCLC (HR, 0.79)12 and advanced squa-mous NSCLC (HR, 0.84), respectively.13 Importantly, our results demonstrate that pembrolizumab plus chemother-apy provides a clinically meaningful OS benefit for patients with PD-L1‒negative NSCLC, a population in need of better treatment options. Although cross-trial comparisons should be approached with caution, the magnitude of ben-efit provided by pembrolizumab plus chemotherapy versus chemotherapy alone in this setting is substantially more pronounced than previously observed with other agents.
The activity of pembrolizumab (an anti‒PD-1 monoclonal antibody) plus chemotherapy among pa-tients whose tumors did not express PD-L1 at the baseline demonstrated the combined effects of immunotherapy and chemotherapy in the NSCLC setting. As noted previ-ously, chemotherapy agents can have immunomodulating
effects that increase the immunogenicity of tumors; the addition of pembrolizumab may, therefore, enhance these immunomodulating effects, regardless of PD-L1 expression.4,5
In addition to the improvements in OS, PFS, and ORR, pembrolizumab plus chemotherapy improved PFS-2 in comparison with chemotherapy alone, and this demonstrated that the benefits of first-line pembroli-zumab plus chemotherapy were maintained through the next line of therapy. The HR for PFS-2 (0.57) was lower than that for PFS (0.68) despite the high rate of cross-over to anti–PD-(L)1 therapy (57.4%) among patients who initially received chemotherapy alone; this supports preferential use of first-line pembrolizumab plus chemo-therapy in PD-L1‒negative NSCLC. The early and con-tinued separation in both PFS curves over time indicates that early disease control with pembrolizumab plus che-motherapy is important in achieving a long-term clinical benefit. In addition, the OS and PFS observed after on-study crossover from chemotherapy to pembrolizumab monotherapy were modest (~6 and ~3 months, respec-tively), and this further supports the need to administer pembrolizumab as part of first-line combination therapy.
In an exploratory analysis of part 1 of CheckMate 227, among patients with PD-L1‒negative NSCLC, nivolumab plus chemotherapy improved PFS in compar-ison with chemotherapy alone (HR, 0.74; 95% CI, 0.58-0.94),14 and nivolumab plus ipilimumab improved OS in comparison with chemotherapy (HR, 0.62; 95% CI, 0.48-0.78).15 Subsequently, part 2 showed no OS benefit with nivolumab plus chemotherapy versus chemotherapy alone in the all-comers nonsquamous NSCLC popula-tion.16 Similarly, in IMpower-132 and IMpower-130, atezolizumab added to a platinum doublet showed bene-fit in patients with nonsquamous NSCLC, regardless of PD-L1 status.17,18
Overall, pembrolizumab plus chemotherapy had manageable toxicity, although the proportion with grade 5 treatment-related AEs was higher in the pembrolizumab plus chemotherapy group than the chemotherapy alone group. No new safety signals were observed in this pooled population of patients with PD-L1‒negative tumors with respect to AEs previously associated with the combination of pembrolizumab and platinum-based chemotherapy in advanced NSCLC.6-8
This pooled analysis of individual patient data pro-vides a large population for an evaluation of the efficacy and safety of pembrolizumab plus platinum-based che-motherapy in patients with PD-L1‒negative tumors. In each of the parent studies, PD-L1 was a prospectively
TABLE 2. Summary of Confirmed ORRs Assessed According to RECIST Version 1.1 by Blinded, Independent, Central Review in a Pooled Analysis of Patients With a PD-L1 TPS < 1%
Abbreviations: DOR, duration of response; ORR, objective response rate; PD-L1, programmed death ligand 1; RECIST, Response Evaluation Criteria in Solid Tumors; TPS, tumor proportion score.aIncludes confirmed complete responses plus partial responses.bIncludes patients with 1 or more postbaseline tumor assessments, none of which were evaluable for response, and those with a postbaseline tumor assessment less than 6 weeks from randomization showing a complete re-sponse, a partial response, or stable disease.cNo postbaseline assessment was available for a response evaluation.dA plus sign indicates no progressive disease at the time of the last disease assessment.eIncludes patients who were alive and had not progressed, initiated new anti-cancer treatment, or been lost to follow-up with a last adequate assessment less than 5 months before the data cutoff date.
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evaluated stratification factor, and this allowed the ret-rospective pooled analysis to be conducted. Although the chemotherapy regimens differed between the studies, each study included standard platinum-based regimens recommended according to NSCLC his-tology.19 Because of the 2:1 randomization ratio in KEYNOTE-189, the proportion of patients with non-squamous histology was higher in the pembrolizumab plus chemotherapy group than the chemotherapy alone
group. Notably, the direction of the treatment effect was similar in both patients with squamous NSCLC and patients with nonsquamous NSCLC (albeit with a dif-ferent magnitude). The HR for OS in the current pooled analysis favoring pembrolizumab plus chemotherapy over chemotherapy alone compared closely with re-sults for the PD-L1–negative subgroups of the primary analyses of the KEYNOTE-189 and KEYNOTE-407 studies7,8 (HR point estimates for OS, 0.63 [pooled],
TABLE 3. All-Cause Adverse Events in Patients With a PD-L1 TPS < 1%
Pembrolizumab + Chemotherapy (n = 255), No. (%)
Chemotherapy Alone (n = 186), No. (%)
Any Grade Grade 3-5 Any Grade Grade 3-5
Any event 253 (99.2) 182 (71.4) 184 (98.9) 134 (72.0)Event leading to discontinuation of study drug 93 (36.5) 64 (25.1) 31 (16.7) 24 (12.9)Event leading to death 27 (10.6) 27 (10.6) 12 (6.5) 12 (6.5)Event leading to treatment-related death 13 (5.1) 13 (5.1) 3 (1.6) 3 (1.6)Event occurring in ≥20% of patients in either group
Abbreviations: PD-L1, programmed death ligand 1; TPS, tumor proportion score.Events are included regardless of attribution to the study drug or immune relatedness by the investigator.aTwo patients in the pembrolizumab plus chemotherapy group had events of pneumonitis that led to death. There were no immune-mediated adverse events or infusion reactions leading to death in the chemotherapy group.
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0.59 [KEYNOTE-189; nonsquamous], and 0.61 [KEYNOTE-407; squamous]). This pooled analysis represents the largest evaluation of outcomes with an immunotherapy plus chemotherapy combination in pa-tients with PD-L1‒negative advanced NSCLC, and the outcomes described provide an important benchmark for comparison with outcomes in future studies.
In conclusion, this pooled analysis showed clini-cally meaningful improvements in OS, PFS, and ORR and manageable safety with pembrolizumab plus che-motherapy versus chemotherapy alone in patients with PD-L1‒negative advanced NSCLC. Pembrolizumab plus platinum-based chemotherapy is a standard-of-care first-line therapy for patients with advanced squamous or nonsquamous NSCLC, including patients with PD-L1‒negative tumors.
FUNDING SUPPORTFunding for this research was provided by Merck Sharp & Dohme Corp, a subsidiary of Merck & Co., Inc. (Kenilworth, New Jersey).
CONFLICT OF INTEREST DISCLOSURESHossein Borghaei receives partial support from the National Institutes of Health (P30 CA006927); has received clinical trial research sup-port from Millennium Pharmaceuticals, Merck, Celgene, Bristol-Myers Squibb, and Lilly; has served on an advisory board or as a consultant for Bristol-Myers Squibb, Lilly, Genentech, Celgene, Pfizer, Merck, EMD Serono, Boehringer Ingelheim, AstraZeneca, Novartis, Genmab, Regeneron, BioNTech, Cantargia AB, Amgen, AbbVie, Axiom, PharmaMar, Takeda, Huya Bioscience International, GLG Pharma, and Daiichi-Sankyo; has served on data and safety monitoring boards for the University of Pennsylvania chimeric antigen receptor T-cell program, Takeda, and Incyte; has served on scientific advisory boards for Sonnet BioTherapeutics and Rgenix; owns stock in Sonnet BioTherapeutics and Rgenix; and is an employee of Fox Chase Cancer Center. Corey J. Langer has served as a consultant for/received honoraria from Boehringer Ingelheim, Novocure, AstraZeneca, Takeda, Genentech/Roche, Merck, Gilead Sciences, GlaxoSmithKline, OncLive, Takai, and RTP; has re-ceived research funding from Advantagene, AstraZeneca, Genentech/Roche, Lilly, Takai, Trizell, Merck, Takeda, and Inovio Pharmaceuticals; has received medical writing support from Novartis; and has served on data and safety monitoring committees for Lilly, Amgen, and SWOG. Luis Paz-Ares reports honoraria (to him/spouse) for scientific advice or speaking from Advanced Accelerator Applications (Adacap), Amgen, AstraZeneca, Bayer, Blueprint Medicines, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Incyte, Ipsen, Lilly, Merck, MSD, Novartis, PharmaMar, Pfizer, Roche, Sanofi, Servier, Takeda, and Sysmex; is a board member for Genomica and Altum Sequencing; and reports grants to his institution from AstraZeneca, Bristol-Myers Squibb, MSD, and Pfizer. Delvys Rodríguez-Abreu reports grants from Bristol-Myers Squibb and has received honoraria for lectures and consulting from Bristol-Myers Squibb, Genentech/Roche, MSD, AstraZeneca, Boehringer Ingelheim, Lilly, Roche, Novartis, and Pfizer. Balazs Halmos has received research funding from Amgen, Janssen, Advaxis, Merck, Bristol-Myers Squibb, Boehringer-Ingelheim, Lilly, Novartis, GlaxoSmithKline, Pfizer, AbbVie, AstraZeneca, Mirati Therapeutics, Takeda, and Guardant Health; has served as a consultant for Merck, Novartis, Boehringer Ingelheim, AstraZeneca, Novartis, Pfizer, Guardant Health, Spectrum, Bristol-Myers Squibb, and Genentech; and has received personal fees from Amgen and TPT. Marina C. Garassino has received grants and personal fees for clinical trials from AstraZeneca, Novartis, Bristol-Myers Squibb, Roche, Pfizer, Celgene, Bayer, and MSD;
grants from Turning Point, Ipsen, MedImmune, Exelixis, Incyte, Lilly, Otsuka Pharmaceutical, Tiziana Life Sciences, Clovis Oncology, Merck Serono, Merck KGaA, Blueprint Medicine, GlaxoSmithKline, United Therapeutics Corporation, and Spectrum Pharmaceuticals; personal fees from Seattle Genetics, Daiichi Sankyo, GlaxoSmithKline, Lilly, Janssen, Boehringer Ingelheim, Blueprint Medicine, Otsuka Pharmaceutical, Incyte, Inivata, Spectrum Pharmaceuticals, Takeda, and Sanofi-Aventis; and nonfinancial support from MSD, Pfizer, and Lilly. Takayasu Kurata has received honoraria from AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Chugai, Lilly, MSD, and Ono Pharmaceutical and reports grants from AstraZeneca, MSD, Bristol-Meyers Squibb, Novartis, Takeda, and Chugai. Jianxin Lin is an employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, New Jersey, USA. M. Catherine Pietanza is an employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, New Jersey, USA and owns stock in Merck & Co., Inc., Kenilworth, New Jersey, USA. Bilal Piperdi is an employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, New Jersey, USA. and owns stock in Merck & Co, Inc., Kenilworth, New Jersey, USA. Shirish M. Gadgeel has received personal fees from AstraZeneca, Daichii-Sankyo, Genentech/Roche, Takeda/Ariad, Boehringer Ingelheim, Merck, Novocure, Bristol-Myers Squibb, AbbVie, Jazz Pharmaceuticals, and Xcovery. The other authors made no disclosures.
AUTHOR CONTRIBUTIONSHossein Borghaei: Investigation, resources, and writing–review and edit-ing. Corey J. Langer: Investigation, resources, and writing–review and editing. Luis Paz-Ares: Investigation, resources, and writing–review and editing. Delvys Rodríguez-Abreu: Investigation, resources, and writing–review and editing. Balazs Halmos: Investigation, resources, and writing– review and editing. Marina C. Garassino: Investigation, resources, and writing–review and editing. Baerin Houghton: Investigation, resources, and writing–review and editing. Takayasu Kurata: Investigation, resources, and writing–review and editing. Ying Cheng: Investigation, resources, and writing–review and editing. Jianxin Lin: Formal analysis and writing‒review and editing. M. Catherine Pietanza: Conceptualization, investigation, and writing‒review and editing. Bilal Piperdi: Conceptualization, investigation, and writing–review and edit-ing. Shirish M. Gadgeel: Investigation, resources, and writing–review and editing.
DATA AVAILABILITYThe data sharing policy, including restrictions, of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. (Kenilworth, New Jersey), is avail-able at http://engag ezone.msd.com/ds_docum entat ion.php. Requests for access to the clinical study data can be submitted through the EngageZone site or via email to [email protected].
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